siRNAs silence or suppress specific genes utilizing an endogenous pathway common to all cells. Since particular tumor cells are exquisitely sensitive to the silencing of certain genes, siRNAs offer the prospective of a general gene-specific approach to the treatment of cancer. The major barrier to the use of siRNAs therapeutically is delivery of these agents to the cytoplasm of tumor cells. This program will explore the design of multifunctional nanoparticles which will enhance the pharmacokinetics of siRNAs, target them to tumor cells, promote their uptake by cells, and their release into the cytoplasm. Two complementary approaches will be explored to enhance the therapeutic potential of siRNA. In one project, siRNAs will be attached to the surface of nanoparticles (semiconductor quantum dots) together with: peptides targeted to specific tumor cells, polyethylene glycol to limit uptake by the reticuloendothelial system, and agents to promote endosomal escape. Identification of novel targeting peptides to glioblastoma, lung adenocarcinoma and their stem cells, and peptides that facilitate transport across the blood-brain barrier will be done in collaboration with the Ruoslahti lab. siRNA may require protection from serum and tissue nucleases. Therefore, in a second project in collaboration with the Langer lab, siRNAs will be incorporated into polymeric nanoparticles that enhance their uptake and release into the cytoplasm. Specifically, a combinatorial polymer library will be screened in a high-throughput format to identify materials for efficient, non-toxic delivery to tumors. Because this is a new therapeutic approach where several basic technologies must be explored, we will concentrate in this program on testing the effectiveness of siRNAs in two murine tumor models: a glioblastoma generated by activation of a ROS tyrosine kinase receptor oncogene, and a murine lung adenocarcinoma generated by activation of the K-ras oncogene. There are several advantages in using these models: the tumors develop in the context of their normal organ tissue, the tumors are more homogenous than human cancers, and the biology of the tumors'response to treatment, such as the role of stem cells, can be explored. The project therefore combines sophisticated tumor models with two complementary nanoparticle-based approaches to cancer therapy. If successful, this research could be direcly translated to human disease and could revolutionize cancer treatment.